Discovering a Combination Therapeutic Approach to Use in the Treatment of Cryptoc

描述（由申请人提供）：隐球菌病是一种主要由新型隐球菌引起的破坏性机会性感染。隐球菌病最常扩散到大脑，引起隐球菌性脑膜炎（CM），如果不及时治疗是致命的。CM是艾滋病的中枢神经系统（CNS）疾病，在全世界60-70%的HIV阳性个体中发生。在撒哈拉以南非洲，CM每年导致50多万艾滋病毒阳性患者死亡，而总人口中每年因结核病死亡的人数为35万。CM的症状包括严重恶心、脑膜炎症引起的头痛、精神状态改变和发烧。无法获得推荐的两性霉素B/氟胞嘧啶（AmB/氟胞嘧啶）一线治疗组合是发展中国家高死亡率的一个关键因素。在这种情况下，由于这些药物缺乏口服配方，需要在医院进行静脉注射，从而阻碍了这些药物的获取。此外，在北美，感染艾滋病毒的急性CM患者在感染后3个月内的死亡率超过20%，尽管患者可以获得AmB/氟胞嘧啶。氟康唑是一种口服抑菌药物，在AmB/氟胞嘧啶初始治疗后使用，通常在诱导治疗后使用数月。2011年，仅吉利德的脂质体Ambisome B（不包括仿制药AmB）的销售额就达到3.3亿美元，而在2003年之前，氟康唑的年销售额超过10亿美元。通过采用一种新的杀真菌化合物筛选方法，我们鉴定出了几种针对新生C. Pkh2-02激酶的分子。初步数据显示口服Pkh2-02激酶抑制剂联合氟康唑具有杀真菌活性，我们计划创造一种新的有效治疗CM的方法。目的1。利用初始文库筛选结果和SAR设计Pkh2-02抑制剂Aim 2小文库。筛选和选择单一治疗和与氟康唑（FL）或泊沙康唑（POS）联合治疗的抗真菌活性化合物，评估初始pk特性和细胞毒性，并根据观察到的SAR迭代文库。根据需要迭代库，根据Aim 2的结果生成额外的40个化合物，以重新聚焦库并执行更详细的pk和pd筛选。

DESCRIPTION (provided by applicant): Cryptococcosis is a devastating opportunistic infection caused primarily by Cryptococcus neoformans. Cryptococcosis most often spreads to the brain, causing cryptococcal meningitis (CM), and is fatal if left untreated. CM is the AIDS-defining central nervous system (CNS) illness and occurs in 60-70% of HIV positive individuals worldwide. In sub-Saharan Africa, CM causes more than 500,000 annual deaths among HIV positive patients compared with 350,000 annual fatalities for tuberculosis in the overall population. CM presents with symptoms including severe nausea, headache due to inflammation of the meninges, altered mental status, and fever. Lack of access to the recommended first-line therapeutic combination of amphotericin B/flucytosine (AmB/flucytosine) is a key component of the high mortality rate in the developing world. Access in this setting is hindered by the need for hospital-based i.v. administration of these drugs which lack an oral formulation. Moreover, the mortality rate for HIV-infected acute CM patients is over 20% within 3 months after infection in North America, despite patient access to AmB/flucytosine. Fluconazole, an oral, fungistatic drug, is used after the initial treatment with AmB/flucytosine, and is often used for months after induction therapy. Sales of Gilead's liposomal Ambisome B alone (not counting generic AmB) were $330 million in 2011 while sales of fluconazole exceeded $1 billion annually, prior to 2003. By employing a novel screen for fungicidal compounds, we identified several molecules that target C. neoformans Pkh2-02 kinase. Encouraged by preliminary data demonstrating that orally available Pkh2-02 kinase inhibitors combined with fluconazole have fungicidal activity, we plan to create a novel and efficacious treatment for CM. Aim 1. Employ initial library screening results and SAR to design a small library of Pkh2-02 inhibitors Aim 2. Screen and select compounds for antifungal activity against strains of C. neoformans as monotherapy and combined with fluconazole (FL) or posaconazole (POS), evaluate initial pk properties and cytotoxicity, and iterate library based on observed SAR. Aim 3. Iterate library as needed to generate an additional 40 compounds based on the Aim 2 results to refocus library and perform more detailed pk and pd screens.